ES2302658B1 - PREPARATION OF DERIVATIVES OF INSOTIAZOLINONA N-SUBSTITUTES. - Google Patents

Abstract

Preparation of isothiazolinone derivatives N-substituted

A procedure is provided for preparation of an isothiazolinone derivative N-substituted which has the general formula (I), which comprises reacting 3-mercaptopropionamides N-substituted formula (II) or 3,3'-dithiodipropionamides N, N'-bis-substituted formula (III) with sulfuryl chloride in the absence of solvents. Be it also provides a procedure for the preparation of a compound having the general formula (III), which comprises making reacting a methyl ester of formula (IV) with an amine of formula (V) in a methanol solvent. Because it is not used solvent addition in the process of the invention can be reduce the cost of production and pollution of the environment ambient.

Description

Preparation of isothiazolinone derivatives N-substituted

Field of the Invention

The present invention relates to the preparation of isothiazolinone derivatives, and more specific, to the preparation of isothiazolinone derivatives N-substituted

Background of the invention

Isothiazolinone compounds are a type new of powerful and broad spectrum antiseptics that possess the Advantages of high potency, low toxicity, a long period effective and safe for the environment against conventional antiseptics Therefore, the compounds of Isothiazolinone have wide applications in the fields of water treatment, cosmetics, building materials, binders, paints, medical treatment, tissues, photographs and detergents, and can be used especially as agents antifouling coatings marine antifouling

So far a number of procedures for the preparation of isothiazolinone derivatives N-substituted, most of them they comprise the step of reacting a dithiodipropionamide N, N'-bis-substituted or a N-substituted mercaptopropionamide with an agent of halogenation in an organic solvent.

For example, Chinese patent applications CN1634889 and CN1629148 describe, respectively, procedures for the preparation of N-alkoxypropylisothiazolinones  and N-alkoxyethoxypropylisothiazolinones, which understand react the corresponding dithiodipropionamides N, N'-bis-substituted with chloride sulfuryl in ethyl acetate.

The Japanese patent application JP2003-335763 describes a procedure for preparation of 4-isothiazolin-3-ones  2-substituted, which comprises reacting N-substituted mercaptopropionamides or dithiodipropionamides N, N'-bis-substituted with an agent of halogenation in ethyl acetate.

European patent application EPO498347 describes a procedure for the preparation of 2-methyl-isothiazolin-3-ones,  which includes reacting N-methyl-3-mercaptopropionamides  with chlorine in an aromatic or halogenated hydrocarbon solvent, such as benzene, toluene, chlorobenzene, chloroform and Similar.

European patent application EP1113012 describes a procedure for the preparation of 2-alkyl-4-isothiazolin-3-ones,  which includes reacting N-alkylmercaptopropionamides or N, N'-dialkyl dithiopropionamides with an agent of chlorination in a solvent, in which hydrogen chloride is insoluble or has low solubility, such as hydrocarbons halogenated aliphatics, halogenated aromatic hydrocarbons or Aliphatic hydrocarbons.

US 5,453,507 describes a procedure for the preparation of N, N'-dimethyl or N, N'-di-n-octyl-4-isothiazolin-3-ones, which comprises reacting dithiodipropionamides N, N'-bis-substituted with chloride sulfuryl in a halogenated organic solvent, such as CH 2 X 2, CHX 3, CX 3 CH 3 and CHX2CHX2.

However the use of organic solvents in prior art procedures causes a great number of problems For example, first of all the use of solvent will reduce the volumetric efficiency of the reactor with what that decreases productivity; second the post-treatment and solvent recovery will increase the cost of operation; third solvent will bring impurities to the reaction system which complicates the separation and purification of the desired products; and finally the organic solvent used, especially benzene e halogenated hydrocarbons, usually has an adverse effect on environment.

Summary of the Invention

The present invention is directed to provide an improved procedure for the preparation of derivatives of N-substituted isothiazolinone, which is more economical and  Less harmful to the environment.

According to one aspect of the invention, provides a process for the preparation of a compound that It has the following general formula (I),

one

in the that

R1 is selected from the group consisting of alkyl, cycloalkyl and aryl, optionally substituted with a substituent selected from the group consisting of alkyl, aryl, alkoxy and aryloxy; Y

R 2 and R 3, each represent independently, hydrogen or chlorine,

which includes:

react a compound that has the following general formula (II),

2

in which R1 is as defined previously,

or a compound that has the following formula general (III),

3

in which R1 is as defined previously,

with sulfuryl chloride in the absence of a solvent

According to a preferred embodiment of the invention, R1 is selected from the group consisting of alkyl C 1 -C 8, cycloalkyl C 3 -C 8 and aryl C 6 -C 10, optionally substituted with a substituent selected from the group consisting of alkyl C 1 -C 8, aryl C 6 -C 10, alkoxy C_ {1} -C_ {8} and aril C 6 -C 10 -oxy. Plus preferably, R 1 represents alkyl C 1 -C 8 optionally substituted with aryl C 6 -C 10 or alkoxy C_ {1} -C_ {8}.

According to another preferred embodiment of the invention, R2 and R3 both represent hydrogen or chlorine.

Preferably the reaction is carried out at a temperature between about -10 ° C and about 75 ° C, and more preferably between room temperature and about 45 ° C

In accordance with the process of the invention Isothiazolinone derivatives can be prepared N-substituted in the absence of a solvent, and by both can avoid problems caused by the use of a Organic solvent in the prior art, and can be reduced by large extent the cost of production and pollution of the environment ambient.

According to another aspect of the invention, provides a process for the preparation of a compound which has the following general formula (III), which comprises the step of reacting a compound of formula (IV),

4

with a compound that has the General Formula (V),

(V) H 2 N - R1

in which R1 is as defined previously,

in a methanol solvent.

According to a preferred embodiment of this  procedure in the invention, the molar ratio of the compound of formula (IV) to the compound of formula (V) is between approximately 1: 2.0 and 1: 2.6. The reaction temperature is preferably between about -15 ° C and about 65 ° C.

According to the process of the invention,  no more impurities will be generated in the reaction system during the preparation of the compound of formula (III), and the separation and purification of it can be greatly simplified in comparison with prior art procedures.

Detailed description of the invention

As described above, in one aspect of the invention, a method is provided for preparation of an isothiazolinone derivative N-substituted which has the following general formula (I),

5

in the that

R1 is selected from the group consisting of alkyl, cycloalkyl and aryl, optionally substituted with a substituent selected from the group consisting of alkyl, aryl, alkoxy and aryloxy; Y

R 2 and R 3, each represent independently, hydrogen or chlorine,

comprising the step of reacting a N-substituted 3-mercaptopropionamide which has the general formula (II),

6

in which R1 is as previously defined, or

a 3,3'-dithiodipropionamide N, N'-bis-substituted which has the following general formula (III),

7

in which R1 is as of defined previously,

with sulfuryl chloride in the absence of a solvent

The term "alkyl", as used in This invention generally refers to a hydrocarbon group aliphatic, saturated, linear or branched, preferably alkyl C 1 -C 10, and more preferably alkyl C 1 -C 8, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.

The term "cycloalkyl", as used In this invention, it generally refers to a group saturated alicyclic hydrocarbon, preferably cycloalkyl C 3 -C 10, and more preferably cycloalkyl C 3 -C 8, such as cyclopropyl, cyclobutyl, cyclopentyl and the like.

The term "aryl", as used in this  invention generally refers to a hydrocarbon group aromatic, preferably C 6 -C 20 aryl, more preferably C 6 -C 10 aryl, such as phenyl and naphthyl, and most preferably phenyl.

The term "in the absence of a solvent", as used in this invention, means that, except for reactants as such, no other substances are added to the system reaction to dissolve the reactants, intermediates or products.

During the preparation of derivatives of isothiazolinone according to the process of the invention, the sulfuryl chloride acts in the reaction system as much as the reactant as the solvent at the beginning of the reaction; and once sulfuryl chloride, the isothiazolinone derivative is depleted resulting acts as a solvent, and therefore is not needed solvent addition.

In particular embodiments of the invention,  you can separate the desired product using well known techniques which includes, but is not limited to, recrystallization and solvent extraction.

In a preferred embodiment of the invention, R 1 represents C 1 -C 8 alkyl optionally substituted with C 6 -C 10 aryl or C 1 -C 8 alkoxy. More preferably, R 1 represents C 1 -C 8 alkyl, especially n-octyl.

In another preferred embodiment of the invention, R 2 and R 3 represent both hydrogen or chlorine.

In some preferred embodiments the method of the invention comprises reacting a compound of formula (II) with sulfuryl chloride. Plus preferably, the molar ratio of the compound of formula (II) to sulfuryl chloride is between about 1: 1 and 1:11.

In other embodiments of the invention, it can be  use chlorine in addition to sulfuryl chloride as an agent of chlorination

In a preferred embodiment, the process of the invention comprises reacting a compound of formula (III) with sulfuryl chloride optionally in the presence of chlorine. More preferably, the molar ratio between the compound of formula (III), sulfuryl chloride and chlorine is approximately 1: 1-11: 0-11, and even more preferably approximately 1: 1-3: 5-7.

In a particularly preferred embodiment the method of the invention further comprises the step of preparing a compound of formula (III), which comprises reacting Dimethyl 3,3'-dithiopyropionate of formula (IV).

       \ vskip1.000000 \ baselineskip
    

8

       \ vskip1.000000 \ baselineskip
    

with an amine that has the formula general (V),

(V) H 2 N - R1

in which R1 is as defined previously,

in a methanol solvent.

More preferably, the molar ratio of compound of formula (IV) to compound of formula (V) is between approximately 1: 2.0 and 1: 2.6. The reaction temperature between the compound of formula (IV) and the compound of formula (V) is preferably between -15 ° C and about 65 ° C, and more preferably between about 5 ° C and room temperature. The reaction time is about 3 hours to 5 days.

       \ newpage
    

In another aspect of the invention is provided a process for the preparation of a compound of formula (III), which comprises reacting Dimethyl 3,3'-dithiopyropionate of formula (IV),

       \ vskip1.000000 \ baselineskip
    

9

       \ vskip1.000000 \ baselineskip
    

with an amine that has the formula general (V),

(V) H 2 N - R1

in which R1 is as defined previously,

in a methanol solvent.

Preferably, R 1 represents alkyl C 1 -C 8 optionally substituted with aryl C 6 -C 10 or alkoxy C_ {1} -C_ {8}. More preferably, R1 represents C 1 -C 8 alkyl, especially n-octyl.

And preferably, the molar ratio of compound of formula (IV) to compound of formula (V) is between approximately 1: 2.0 and 1: 2.6. The reaction temperature is preferably between about -15 ° C and about 65 ° C, and more preferably between about 5 ° C and temperature ambient. The reaction time is about 3 hours at 5 days.

Since methanol is a reaction product between the compound of formula (IV) and the compound of formula (V), the use of methanol as a solvent in the process of invention would not introduce impurity into the reaction system no desired some. Thus, the separation and purification of the product desired can be greatly simplified. More specific, compared to procedures in which it is used water as a solvent, the product obtained according to the method of the invention has a larger particle size and therefore it can be easily separated from the mother liquor. And agree with the process of the invention the liquor can be recycled mother left and methanol can be recovered by evaporation. As a result the emission of waste to the environment Environment is greatly reduced.

       \ vskip1.000000 \ baselineskip
    

Examples

In the following, embodiments will be illustrated of the invention in detail in reference to the following examples, which should be considered only by title Illustrative and not limiting.

       \ vskip1.000000 \ baselineskip
    

Example one

Preparation of N, N'-di-n-octyl-3,3'-dithiodipropionamide

The reaction scheme is as follows:

(SCH 2 CH 2 CO 2 CH 3) 2 + 2C_ {8} H17 {NH2} \ longrightarrow (SCH 2 CH 2 CONHC 8 H 17) 2 + 2CH 3 OH

238 g (1 mol) of dimethyl were added 3,3'-dithiodipropionamide and 280 g (2.17 mol) of n-octylamine to 300 ml of methanol in a flask 1000 ml reaction, and the reactants were stirred at 5 ° C for 5 days (under nitrogen atmosphere, if desired). It cooled then the reaction mixture to -10 ° C, and separated by centrifugation giving 329 g of a solid of N, N'-di-n-octyl-3,3'-dithiodipropionamide  (purity> 95%, yield 76%). The mother liquor was recycled once methanol was recovered by evaporation.

       \ newpage
    

Example 2

Preparation of N-n-Octyl isothiazolinones (including N-n-octyl-4-isothiazolin-3-one  (ILO) and N-n-octyl-4,5-dichloro-4-isothiazolin-3-one (DCOIT))

The reaction scheme is as follows:

10

200 ml (330 g, 2.44 mol) of chloride was added of sulfuryl in a 1,000 ml reaction flask, to which was added then 648 g (1.5 mol) of N, N'-di-n-octyl-3,3'-dithiodipropionamide  for 6.5 hours (approximately 100 g per hour) under agitation. After 3 hours of reaction, chlorine was circulated in the reaction mixture at about 50 g per hour for 13 hours (approximately 650 g in total, 9.15 mol). When the temperature of the reaction mixture reached 40 ° C, the mixture with saline solution and kept at a temperature of 40 to 45 ° C Once the chlorine circulation was completed, the reaction mixture at the same temperature for 2 hours.

The reaction mixture was washed with hot water. at 50 ° C in another 1,000 ml reaction flask until it began to become weakly acidic, and, if desired, used Baking soda to neutralize excess acidity. Be recrystallized the precipitate in methanol giving 190 g of DCOIT (purity > 95%). The mother liquor was then extracted from the recrystallization successively with petroleum ether and methanol giving 61 g of ILO (purity> 93%, yield 19%) and 49 g of DCOIT (purity> 95%) The total yield of DCOIT is 56.5%.

It should be understood that although present invention has been described specifically with the embodiments preferred and examples, modifications and variations thereof without departing from the spirit of the invention, by those skilled in the art, and such modifications and variations should be found within the scope of the invention.

Claims (13)

1. A procedure for the preparation of a compound having the following general formula (I), eleven in the that R1 is selected from the group consisting of C 1 -C 8 alkyl, cycloalkyl C 3 -C 8 and aryl C 6 -C 10, optionally substituted with a substituent selected from the group consisting of alkyl C 1 -C 8, aryl C 6 -C 10, alkoxy C_ {1} -C_ {8} and aril C 6 -C 10 -oxy; Y R 2 and R 3, each represent independently, hydrogen or chlorine, which includes: react a compound that has the following general formula (II), 12 in which RI is as defined previously, or a compound that has the following formula general (III), 13 in which RI is as defined previously, with sulfuryl chloride in absence of a solvent 2. The procedure according to the claim 1, wherein RI represents alkyl C 1 -C 8 optionally substituted with aryl C 6 -C 10 or alkoxy C_ {1} -C_ {8}. 3. The procedure according to the claim 2, wherein R 1 represents alkyl C_ {1} -C_ {8}. 4. The procedure according to the claim 3, wherein R2 and R3 both represent hydrogen or chlorine 5. The procedure according to a any one of claims 1 to 4, wherein the reaction is carried out at a temperature between about -10 ° C and approximately 75 ° C. 6. The procedure according to the claim 5, wherein the method comprises doing reacting a compound of formula (II) with sulfuryl chloride, and  wherein the molar ratio of the compound of formula (II) to sulfuryl chloride is between about 1: 1 and 1:11. 7. The procedure according to the claim 5, wherein the method comprises doing reacting a compound of formula (III) with sulfuryl chloride optionally in the presence of chlorine, and in which the molar ratio between the compound of formula (III), sulfuryl chloride and chlorine It's about 1: 1-11: 0-11. 8. The procedure according to the claim 7, further comprising preparing a compound of formula (III), which comprises reacting, in a solvent of methanol, a compound of formula (IV),

         \ vskip1.000000 \ baselineskip
      

14 with a compound that has the General Formula (V), (V) H 2 N - R1 in which R1 is as defined previously. 9. The procedure according to the claim 8, wherein the molar ratio of the compound of formula (IV) to the compound of formula (V) is between approximately 1: 2.0 and 1: 2.6. 10. The procedure according to the claim 9, wherein the reaction between the compound of formula (IV) and the compound of formula (V) is carried out at a temperature between about -15 ° C and about 65 ° C. 11. A procedure for the preparation of a compound having the general formula (III),

         \ vskip1.000000 \ baselineskip
      

fifteen in the that R1 is selected from the group consisting of C 1 -C 8 alkyl, cycloalkyl C 3 -C 8 and aryl C 6 -C 10, optionally substituted with a substituent selected from the group consisting of alkyl C 1 -C 8, aryl C 6 -C 10, alkoxy C_ {1} -C_ {8} and aril C 6 -C 10 -oxy, which comprises reacting in a solvent of methanol, a compound of formula (IV),

         \ vskip1.000000 \ baselineskip
      

16 with a compound that has the formula (V), (V) H 2 N - R1 in which R1 is as defined previously. 12. The procedure according to the claim 11, wherein the molar ratio of the compound of formula (IV) to the compound of formula (V) is between approximately 1: 2.0 and 1: 2.6. 13. The procedure according to the claim 11 or 12, wherein the reaction between the compound of  formula (IV) and the compound of formula (V) is carried out at a temperature between -15ºC and approximately 65ºC.